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Abstract BRCC3 isopeptidase complex (BRISC) is a JAMM subfamily deubiquitinase that has been revealed to be required for optional activation of NLRP3 inflammasome and TLR4/NF-κB signaling pathway. BRISC plays an important role in lipopolysaccharide (LPS)/D-galactosamine-induced acute liver failure, while its functional contribution to alcoholic liver disease (ALD) is still unclear. In this study, we found that the expression of BRISC components was increased in liver tissues of alcoholic hepatitis (AH) animal models and patients with AH. Mice lacking either the scaffold subunit ABRO1 or the catalytic subunit BRCC3 showed attenuated liver steatosis, inflammation, and liver injury compared to control mice after chronic plus binge ethanol feeding. Moreover, pharmacological inhibition of BRISC activity by a BRISC inhibitor thiolutin potently protected mice from ALD development. Preliminary mechanistical studies showed that BRISC deficiency did not directly affect alcohol-induced hepatocyte injury or the translocation of LPS through the damaged gut mucosa after ethanol feeding, but prevented alcohol-induced NLRP3 inflammasome activation in liver. Collectively, our work revealed a previously unknown role of BRISC in ALD and suggested that BRISC may serve as a promising therapeutic target for ALD treatment.

Holography is an emerging technology where phase-only spatial light modulator (SLM) is better than amplitude-only SLM because of its enhanced diffraction efficiency and rendering quality. However, phase-only interference pattern reconstruction is an ill-posed inverse problem, difficult to solve by standard supervised neural network approaches. Accurately representing the target input during reconstruction of phase-only hologram (POH) can become challenging given the inherent high spatial frequency of phase data and the complexity of its fringe patterns, expressing the inverse nature of the problem. Therefore, the model may be trained improperly, inducing major compromise in the predicted hologram’s quality. As a result, an unsupervised approach can be effective to resolve such a problem. This paper presents a novel combined U2-net-based computer-generated hologram (CUSNet-CGH) architecture, an end-to-end deep learning model comprising two distinctively designed combined convolution networks that accurately generate 2D POH. The proposed framework contains U2-net which is known for performing unsupervised learning tasks without relying on pre-trained backbones from labeled dataset, making it an ideal approach for conducting unsupervised training. The numerical reconstructions are compared with several other state-of-the-art methods such as holoencoder, holonet and CCNN-CGH to verify the enhanced quality. The average PSNR of the proposed end-to-end approach is as high as $\sim ~34$ dB with an average SSIM of 0.91, featured by DIV2K dataset, outperforming the state-of-the-art methods analyzed in the paper. Additionally, the time required to reconstruct the predicted output of the proposed model is verified as competitive, challenging the latest benchmarks, thanks to its minimized number of trainable parameters, and ensuring that the model is computationally lightweight. Finally, experiments also demonstrate that the proposed model yields high-quality optical reconstruction.

Abstract This study aimed to investigate whether lymphocyte-C-reactive protein ratio (LCR) upon admission can predict disease progression and intensive care unit (ICU) admission in adult patients with diabetic ketoacidosis (DKA). A single-center retrospective study was conducted, including adult DKA patients admitted to the First Affiliated Hospital of Harbin Medical University between March 2018 and March 2023. Multiple demographic and clinical data were collected from the medical records upon admission and during hospitalization. Subsequently, sequential organ failure assessment (SOFA) score and LCR were calculated based on relevant clinical parameters within 24 h of admission. These indicators were compared among different disease severity groups, and factors related to severe DKA, concurrent acute kidney injury (AKI), and ICU admission were further analyzed. Receiver operating characteristic (ROC) curve analysis was performed to determine the sensitivity, specificity, area under the ROC curve (AUC), and cut-off value of LCR. A total of 271 adult DKA patients were enrolled and categorized into three groups: mild group (n = 42), moderate group (n = 64), and severe group (n = 165). Significant differences in demographic and clinical data were observed among these groups. Glasgow coma scale (GCS) score, LCR, pH, and bicarbonate (HCO3 -) were identified as protective factors for severe DKA. Conversely, SOFA score, neutrophil count (NEUT), serum creatinine (SCr), and glucose (GLU) were risk factors for concurrent AKI. Concurrent AKI and SOFA score were risk factors for ICU admission, while pH was a protective factor. The areas under the ROC curve (AUC) of LCR to classify adult DKA patients into mild group, severe group, and ICU admission were 0.679, 0.718, and 0.621, respectively, with cut-off value of 212.80, 96.16, and 63.35, sensitivity of 54.8%, 76.4%, and 78.9%, and specificity of 76.0%, 62.4%, and 46.3%. LCR upon admission provides great potential to predict disease progression and ICU admission in adult patients with DKA.

Abstract Metabolic and neurological disorders commonly display dysfunctional branched-chain amino acid (BCAA) metabolism, though it is poorly understood how this leads to neurological damage. We investigated this by generating Drosophila mutants lacking BCAA-catabolic activity, resulting in elevated BCAA levels and neurological dysfunction, mimicking disease-relevant symptoms. Our findings reveal a reduction in neuronal AMP-activated protein kinase (AMPK) activity, which disrupts autophagy in mutant brain tissues, linking BCAA imbalance to brain dysfunction. Mechanistically, we show that excess BCAA-induced mitochondrial reactive oxygen species (ROS) triggered the binding of protein phosphatase 2 A catalytic subunit (PP2Ac) to AMPK, suppressing AMPK activity. This initiated a dysregulated feedback loop of AMPK-mitochondrial interactions, exacerbating mitochondrial dysfunction and oxidative neuronal damage. Our study identifies BCAA imbalance as a critical driver of neuronal damage through AMPK suppression and autophagy dysfunction, offering insights into metabolic-neuronal interactions in neurological diseases and potential therapeutic targets for BCAA-related neurological conditions.

Abstract Pathological neovascularization is a hallmark of many vision-threatening diseases. However, some patients exhibit poor responses to current anti-VEGF therapies due to resistance and limited efficacy. Recent studies have highlighted the roles of noncoding RNAs in various biological processes, paving the way for RNA-based therapeutics. In this study, we report a marked down-regulation of miR-205 under pathological conditions. miR-205 potently inhibits endothelial cell functions critical for pathological neovascularization, including proliferation, migration, and tube formation. Furthermore, miR-205 strengthens the endothelial barrier, thereby reducing vascular leakage. In mouse models of retinal and choroidal neovascularization, miR-205 administration effectively suppresses abnormal blood vessel formation and leakage. Mechanistically, miR-205 directly targets VEGFA and ANGPT2, which are key drivers of pathological neovascularization. To improve delivery, we successfully loaded miR-205 into exosomes derived from mesenchymal stem cells. This innovative approach avoids cytotoxicity while preserving therapeutic efficacy in both cellular and animal models. Collectively, our findings highlight miR-205 as a promising therapeutic for ocular neovascularization, with exosome delivery offering a novel and efficient strategy for treating vision-threatening vascular diseases. Graphical Abstract

Abstract Background Infectious episodes contribute to morbidity and mortality in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Renal involvement, also known as ANCA-associated glomerulonephritis (AGN), is frequently observed in AAV. Little is known about whether co-infection at initial diagnosis is associated with renal outcome and prognosis in children with AGN. Methods Clinical and prognostic data for children admitted to our center with AAV from January 2001 to August 2023 were analyzed retrospectively. We compared the incidence of end-stage renal disease (ESRD) and mortality according to infection status at initial diagnosis. Results A total of 33 children with AGN were included in this study, 22 had an infection at the time of AGN diagnosis. A trend toward higher levels of proteinuria in the infected group than in the non-infected group was observed (p = 0.42). Patients in the infected group had higher creatinine and lower eGFR values than those in the non-infected group (p = 0.09). A significant decrease in HGB was observed in the infected group (p

Adjusting the interfacial transport efficiency of photogenerated electrons and the free energy of hydrogen adsorption through interface engineering is an effective means of improving the photocatalytic activity of semiconductor photocatalysts. Herein, hollow ZnS/NiS nanocages with ohmic contacts containing Zn vacancy (VZn-ZnS/NiS) are synthesized using ZIF-8 as templates. An internal electric field is constructed by Fermi level flattening to form ohmic contacts, which increase donor density and accelerate electron transport at the VZn-ZnS/NiS interface. The experimental and DFT results show that the tight interface and VZn can rearrange electrons, resulting in a higher charge density at the interface, and optimizing the Gibbs free energy of hydrogen adsorption. The optimal hydrogen production activity of VZn-ZnS/NiS is 10,636 μmol h−1 g−1, which is 31.9 times that of VZn-ZnS. This study provides an idea for constructing sulfide heterojunctions with ohmic contacts and defects to achieve efficient photocatalytic hydrogen production.

The exposure of ethanol increases the risk of head and neck inflammation and tumor progression. However, limited studies have investigated the composition and functionality of laryngeal microbiota under ethanol exposure. We established an ethanol-exposed mouse model to investigate the changes in composition and function of laryngeal microbiota using Metagenomic shotgun sequencing. In the middle and late stages of the experiment, the laryngeal microbiota of mice exposed to ethanol exhibited obvious distinguished from that of the control group on principal-coordinate analysis (PCoA) plots. Among the highly abundant species, Salmonella enterica and Mycobacterium marinum were likely to be most impacted. Our findings indicated that the exposure to ethanol significantly increased their abundance in larynxes in mice of the same age, which has been confirmed through FISH experiments. Among the species-related functions and genes, metabolism is most severely affected by ethanol. The difference was most obvious in the second month of the experiment, which may be alleviated later because the animal established tolerance. Notable enrichments concerning energy, amino acid, and carbohydrate metabolic pathways occurred during the second month under ethanol exposure. Finally, based on the correlation between species and functional variations, a network was established to investigate relationships among microbiota, functional pathways, and related genes affected by ethanol. Our data first demonstrated the continuous changes of abundance, function and their interrelationship of laryngeal microbiota under ethanol exposure by Metagenomic shotgun sequencing. Importance: Ethanol may participate in the inflammation and tumor progression by affecting the composition of the laryngeal microbiota. Here, we applied the metagenomic shotgun sequencing instead of 16 S rRNA sequencing method to identify the laryngeal microbiota under ethanol exposure. Salmonella enterica and Mycobacterium marinum are two dominant species that may play a role in the reconstruction of the laryngeal microenvironment, as their local abundance increases following exposure to ethanol. The metabolic function is most evidently impacted, and several potential metabolic pathways could be associated with alterations in microbiota composition. These findings could help us better understand the impact of prolonged ethanol exposure on the microbial composition and functionality in the larynx.

Denervation-induced calcium/calmodulin-dependent protein kinase II (CaMKII) activation and inflammation can result in muscle atrophy. Curcumin and bisdemethoxycurcumin are well known to exhibit an anti-inflammatory effect. In addition, curcumin has been shown to attenuate CaMKII activation in neuronal cells. This study aimed to examine the effect of curcumin or bisdemethoxycurcumin on CaMKII activation, inflammation, and muscle cross-sectional area (CSA) in spinal nerve ligated rats. Sixteen female rats were assigned to sham (CON), spinal nerve ligation (SNL), SNL+ curcumin 100 mg/kg BW (100CUR), and SNL+ bisdemethoxycurcumin 50 mg/kg BW (50CMO) for 4 weeks. Ipsilateral (surgical) soleus and tibialis anterior (TA) muscles was stained for dystrophin to measure CSA. Ipsilateral and contralateral (non-surgical) plantaris muscles were analyzed for protein content for acetylcholine receptor (AChR), CaMKII, CaMKIIThr286, nuclear factor-κB (NF-κB), NF-κBSer536, and interleukin-1β (IL-1β) and normalized to α-tubulin and then CON. A significant (p < 0.050) group effect was observed for TA CSA where CON (11,082.25 ± 1617.68 μm2; p < 0.001) and 100CUR (9931.04 ± 2060.87 μm2; p = 0.018) were larger than SNL (4062.25 ± 151.86 μm2). In the ipsilateral plantaris, the SNL (4.49 ± 0.69) group had greater CaMKII activation compared to CON (1.00 ± 0.25; p = 0.010), 100CUR (1.12 ± 0.45; p = 0.017), and 50CMO (0.78 ± 0.19; p = 0.009). The ipsilateral plantaris (2.11 ± 0.66) had greater IL-1β protein content than the contralateral leg (0.65 ± 0.14; p = 0.041) in the SNL group. In plantaris, the SNL (1.65 ± 0.51) group had greater NF-κB activation compared to CON (1.00 ± 0.29; p = 0.021), 100CUR (0.61 ± 0.10; p = 0.003), 50CMO (0.77 ± 0.25; p = 0.009) groups. The observed reduction in Ca2+ signaling and inflammation in type II plantaris muscle fibers might reflect the changes within the type II TA muscle fibers which may contribute to the mitigation of TA mass loss with curcumin supplementation.

Abstract Background and objectives Maintenance hemodialysis (MHD) patients are at a higher risk of cardiovascular disease (CVD), a common complication and leading cause of death. Persistent micro-inflammation is a unique feature of MHD. Given the established role of inflammation in the pathogenesis of atherosclerosis, this study aims to explore whether novel inflammatory markers (inflammation index) can serve as independent risk factors for CVD in MHD patients. Methods A cross-sectional survey was conducted on patients from three dialysis centers, categorized into a CVD and non-CVD group based on medical history, laboratory tests, and physical examination. Fasting blood samples were collected from all participants for indicator testing. Results The analysis of 209 patients revealed that 104 had concurrent CVD. Patients in the CVD group were significantly older and exhibited higher anxiety and depression scores. Forward stepwise multivariate logistic regression results identified the inflammation index neutrophil-to-lymphocyte ratio (NLR) (OR = 1.27, 95% CI 1.082–1.491, P

Type 2 diabetes (T2D) is associated with increased inflammation and reactive oxygen species (ROS) in muscles, leading to basal satellite cell (SC) myogenic impairment (i.e., reduction in SC pool), which is critical for maintaining skeletal muscle mass. T2D may contribute to muscle atrophy, possibly due to reductions in the SC pool. Geranylgeraniol (GGOH) and ginger can reduce inflammation and enhance SC myogenesis in damaged muscles, thereby alleviating muscle atrophy; however, their effect on basal SC myogenic state and muscle mass in T2D rats is limited. Rats consumed a control diet (CON), high-fat diet with 35 mg/kg of streptozotocin (HFD), a HFD with 800 mg/kg body weight of GGOH (GG), or a HFD with 0.75% ginger root extract (GRE). In the eighth week, their soleus muscles were analyzed for Pax7, MyoD, and MSTN gene and protein expression, SC myogenic state, and muscle cross-sectional area (CSA). The HFD group had a significantly lower number of Pax7+/MyoD− and Pax7+/MSTN+ cells, less Pax7 and MyoD gene expression, and less MyoD and MSTN protein expression, with a smaller CSA than the CON group. Compared to the GG and GRE groups, the HFD group had a significantly lower number of Pax7+/MSTN+ cells, less MyoD protein expression, and smaller CSA. The GRE group also had a significantly lower number of Pax7−/MyoD+ and greater MSTN protein expression than the HFD group. Nevertheless, the CON group had a significantly greater number of Pax7+/MyoD− than the GG and GRE groups, and a greater number of Pax7−/MyoD+ cells than the GRE group with a larger CSA than the GG group. GGOH and ginger persevered muscle CSA, possibly through increased MyoD and the ability to maintain the SC pool in T2D rats.

Abstract Background Infection of mice with mouse-adapted strains of influenza virus has been widely used to establish mouse pneumonia models. Intranasal inoculation is the traditional route for constructing an influenza virus-induced pneumonia mouse model, while intratracheal inoculation has been gradually applied in recent years. In this article, the pathogenicity of influenza virus-induced pneumonia mouse models following intranasal and aerosolized intratracheal inoculation were compared. Methods By comparing the two ways of influenza inoculation, intranasal and intratracheal, a variety of indices such as survival rate, body weight change, viral titer and load, pathological change, lung wet/dry ratio, and inflammatory factors were investigated. Meanwhile, the transcriptome was applied for the initial exploration of the mechanism underlying the variations in the results between the two inoculation methods. Results The findings suggest that aerosolized intratracheal infection leads to more severe lung injury and higher viral loads in the lungs compared to intranasal infection, which may be influenced by the initial site of infection, sialic acid receptor distribution, and host innate immunity. Conclusion Intratracheal inoculation is a better method for modelling severe pneumonia in mice than intranasal infection.

Abstract Background Continuous performance tests (CPTs) are a popular tool for evaluating the symptoms of attention-deficit/hyperactivity disorder (ADHD). Performance measurements are typically linked to the biological features and cognitive functions of individuals. To determine the validity of specific CPT indices in differentiating between school-aged children with ADHD from with non-ADHD, each student’s sex, chronological age, and cognitive abilities should be considered. Methods In this prospective case–control study, a total of 30 non-ADHD students and 26 with ADHD who were aged 6 to 12 years were from general education classrooms. All students completed the Continuous Performance Tests (CPTs) and the Peabody Picture Vocabulary Test-revised (Mandarin-Chinese version). Demographic data were collected from the students’ parents. Results Detectability, Omissions, Commissions, and Hit Reaction Time Standard Deviation (HRT SD) yielded higher T-scores in children with ADHD than those without. Compared with non-ADHD students, those with ADHD had higher classification scores for Detectability, Omissions, Perseverations, and HRT SD. For each CPT index, after individual factors were controlled for, logistic regression revealed that only students with positive scores for Detectability, Omission, and HRT SD (adjusted odds ratios = 4.627, 9.977, and 3.908, Ps

Abstract A/goose/Guangdong/1/96-like (GsGd) highly pathogenic avian influenza (HPAI) H5 viruses cause severe outbreaks in poultry when introduced. Since emergence in 1996, control measures in most countries have suppressed local GsGd transmission following introductions, making persistent transmission in domestic birds rare. However, geographical expansion of clade 2.3.4.4 sublineages has raised concern about establishment of endemic circulation, while mechanistic drivers leading to endemicity remain unknown. We reconstructed the evolutionary history of GsGd sublineage, clade 2.3.4.4c, in Taiwan using a time-heterogeneous rate phylogeographic model. During Taiwan’s initial epidemic wave (January 2015 - August 2016), we inferred that localised outbreaks had multiple origins from rapid spread between counties/cities nationwide. Subsequently, outbreaks predominantly originated from a single county, Yunlin, where persistent transmission harbours the trunk viruses of the sublineage. Endemic hotspots determined by phylogeographic reconstruction largely predicted the locations of re-emerging outbreaks in Yunlin. The transition to endemicity involved a shift to chicken-dominant circulation, following the initial bidirectional spread between chicken and domestic waterfowl. Our results suggest that following their emergence in Taiwan, source-sink dynamics from a single county have maintained GsGd endemicity up until 2023, pointing to where control efforts should be targeted to eliminate the disease.

Abstract Immunity has shown potentials in informing drug development for cardiometabolic diseases, such as type 2 diabetes (T2D) and coronary artery disease (CAD). Here, we performed a transcriptome-wide Mendelian randomization (MR) study to estimate the putative causal effects of 11,021 gene expression profiles during CD4+ T cells activation on the development of T2D and CAD. Robust MR and colocalization evidence was observed for 162 genes altering T2D risk and 80 genes altering CAD risk, with 12% and 16% respectively demonstrating CD4+ T cell specificity. We observed temporal causal patterns during T cell activation in 69 gene-T2D pairs and 34 gene-CAD pairs. These genes were eight times more likely to show robust genetic evidence. We further identified 25 genes that were targets for drugs under clinical investigation, including LIPA and GCK. This study provides evidence to support immune-to-metabolic disease connections, and prioritises immune-mediated drug targets for cardiometabolic diseases.